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Department of Pediatrics, North Shore Long Island Jewish Health System and New York University School of Medicine, Manhasset, NY 11030
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ABSTRACT |
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 TOP ABSTRACT Overview: Interrelationship...Mechanisms involved in the...Interactions of zinc with...Strategies for redressing the...REFERENCES |
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KEY WORDS: • zinc deficiency • malnutrition • diarrhea • nitric oxide • antioxidants
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Overview: Interrelationship among malnutrition, diarrhea and zinc status: malnutrition and diarrhea set the stage for zinc deficiency |
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TOPABSTRACTOverview: Interrelationship...Mechanisms involved in the...Interactions of zinc with...Strategies for redressing the...REFERENCES |
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). The morbidity and mortality rates due to diarrheal
disease are particularly severe in young children. In 1993 there were
~12 million deaths of infants and children < 5 y old, of
which one fourth were related to diarrhea. The vast majority occurred
in developing countries. Fifty-eight percent, or 1.74 million, of
the ~3 million premature deaths due to diarrheal diseases have been
associated with malnutrition (Fuchs 1998
). These
statistics suffice to convey the seriousness of the world public health
problem. In contrast, since 1968 the United States has experienced a
75% decline in diarrheal disease deaths in children < 5 y
old, which now number ~300/y (Kilgore et al. 1995
).
The interaction of factors linking diarrheal episodes, malnutrition and
zinc depletion is diagrammatically presented in Figure 1
. Here we do address immunologic factors associated with zinc
deficiency, which is an area that has been extensively reviewed
(Shankar and Prasad 1998
).
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The discovery of zinc deficiency in humans occurred in populations
characterized by diets based on staples capable of reducing the
bioavailability of metallic elements due to a high concentration of
phytate. Another important and often concurrent feature of these diets
has been their low protein content. This has been a consistent finding,
supported by numerous studies carried out in Asia, Africa and Latin
America (Prasad 1998
). A typical instance of the link
between a low protein intake and zinc deficiency has been documented in
Vietnamese children, of whom 50% experience protein energy
malnutrition during infancy (Ninh et al. 1996
).
Protein-energy malnutrition entails a decrease in the immunologic
defense mechanisms that leads to greater susceptibility to infections,
especially diarrheal disease. Nutritional rehabilitation with a high
protein diet is a difficult task that if inappropriately handled can
result in catastrophic outcome, because the alterations present in the
gastrointestinal tract during severe food restriction can lead to
malabsorption, diarrhea, electrolyte depletion and even death during
recovery. Moreover, the successful assimilation of a high protein diet
demands the additional intake of vitamins and minerals; if not
supplied, clinical deficiencies in one or several of these
micronutrients may ensue (Graham 1993
).
One of the consequences of protein-energy malnutrition is an
alteration in the small intestinal mucosal absorptive capacity for zinc
(Koo and Turk 1977
). In humans, ethical reasons preclude
the documentation of such conditions; data have been obtained only
during nutritional rehabilitation of children with kwashiorkor, a time
when they avidly absorb and retain macronutrients and minerals,
including zinc (McCance et al. 1970
). Experimentally,
the pathophysiology of zinc malabsorption can be observed in
protein-energy–deprived rats, in the presence of low-molecular-weight
ligands such as glycylsarcosine, a hydrolysis-resistant dipeptide
that typifies the protein breakdown products actually absorbed at the
apical membrane of the small intestine. Malnourished rats absorb less
zinc than their well-fed controls (Wapnir et al. 1985
). These reports suggest that a self-perpetuating
situation may develop in which chronic zinc deficiency fosters
malabsorptive conditions that in turn compromise the replenishment of
zinc stores.
Whether it is derived from meat, fish, dairy products, cereals, breads
or vegetables, there is a consistent positive correlation between
protein and the zinc content of foods (Held et al. 1988
,
Wapnir 1990
). The ability of an organism to increase its
zinc stores with adequate or enriched protein feedings is different if
it has previously become zinc depleted. This relationship has been
demonstrated in a study with zinc-deficient and -sufficient rats
fed varying amounts of protein. Tissue zinc concentration increased
linearly with dietary protein in rats fed a zinc-deficient diet. In
contrast, rats fed a zinc-sufficient diet accumulated zinc in their
organs only as dietary protein increased logarithmically
(Oberleas and Prasad 1969
, Wapnir 1990
).
An extreme situation of zinc deficiency not attributable to poor
dietary intake or infection is seen in acrodermatitis enteropathica, a
rare genetic disease often accompanied by diarrhea and poor zinc
retention. Some of the somatic consequences of this disease can be
reversed by vigorous zinc supplementation (Nelder and Hambidge 1975
). Studies on this condition have documented that zinc
deficiency negatively affects the absorption of other nutrients.
Experimentally, zinc-deficient rats exhibit a marked decrease in
water and sodium transport that is not due to a reduced food intake
(Ghishan 1984
).
In Bangladeshi children, it has been shown that increased paracellular
permeability of the intestinal mucosa, an index of abnormal tissue
integrity, caused by proliferating invasive pathogens, such as
Vibrio cholerae and enterotoxigenic Escherichia
coli, is reduced by a supplementation of 5 mg/kg zinc for 2 wk
(Roy and Tomkins, 1989
). Similarly, alterations in
intestinal paracellular permeability induced by a low protein (4%)
diet in guinea pigs could be reversed by the addition of high zinc
concentrations (Rodriguez et al. 1996
). In humans, the
recovery from protein-energy malnutrition with a high protein diet
alone may not be as effective as the same treatment supplemented with
zinc (Shrivastava et al. 1993
). Important caveats have
recently been raised about the amount of supplemental zinc to be
provided. Among children admitted to a nutritional rehabilitation unit
in Bangladesh, those who received 6 mg/kg of zinc for either 15 or
30 d failed to grow at a greater rate than those who received 1.5
mg/kg for 15 d and had a higher mortality rate than the latter
group (Doherty et al. 1998
). The cause of this
unexpected outcome is yet unclear, although the reasons why high zinc
administration may have deleterious effects have been previously
examined (Shankar and Prasad 1998
). At a minimum, the
data suggest that health maintenance and recovery from malnutrition may
not be approached with similar dietary prescriptions.
Growth retardation has been one of the most characteristics features of
zinc deficiency in children, as it is in protein-energy
malnutrition (Prasad 1998
). However, zinc
supplementation by itself does not necessarily produce the linear
growth and weight recuperation needed for catch up (Rosado et al. 1997
, Walravens et al. 1989
). It is
difficult to discriminate between the respective contributions of
general nutritional rehabilitation and zinc supplementation during
recovery from malnutrition and concomitant zinc deficiency. For
example, in a study of children recovering from shigellosis, the
effects attributable to a high protein diet could not be separated from
the inherent increase in zinc intake. The diet providing additional
protein also had more zinc, iron, calcium and vitamin A. While
accelerating growth during a follow-up period, it had a marginal
effect on the frequency of diarrheal episodes as well as respiratory
and febrile illnesses (Kabir et al. 1998
). The more
rapid recuperation of this type of patients has also been attributed to
an improved condition of the intestinal mucosa, which allowed for more
effective absorption of nutrients (Kabir et al., 1994
).
Many zinc supplementation trials have been carried out since the 1980s.
Results have been evaluated in regard to diarrhea duration and, if
observations were carried out for longer periods, rate of growth. Data
were further assessed by meta-analysis and combined analysis
(Black 1998
, Brown et al. 1998
). The most
significant feature is that zinc supplementation has a positive effect
on the duration and severity of diarrheal episodes and a lesser effect
on height and weight. Children who were short at the beginning of the
study benefited from zinc supplementation, whereas those of normal
height did not. Similarly, there was an inverse relationship between
initial plasma zinc and the benefit accrued by zinc administration.
Severe zinc deficiency is associated with anorexia, which in turn may
impede nutritional rehabilitation. The mechanism by which this occurs
is unclear. Recent work indicates that the organism may attempt to
stimulate food intake by increasing the release of an orexigenic
neurohormone, neuropeptide Y
(NPY).2
It appears as if the number of NPY receptors is not reduced by zinc
deficiency. Preservation of hypothalamic NPY receptors has been
demonstrated in zinc-depleted rats (Lee et al. 1998
). Therefore, other signals may be operating in the
observed appetite reduction in humans with zinc deficiency.
Effect of diarrhea on zinc status: contribution of macronutrients.
Diarrheal disease in infants <1 y lasting 
10 d results in abnormally
low concentrations of serum zinc, which inversely correlate with
duration of the disease (Naveh et al. 1982
). Persistent
diarrhea, i.e., a condition lasting >14 d (Black and Sazawal 1998
), or repeated episodes of acute gastroenteritis trigger a
cascade of deleterious effects discussed later. It appears that a
vicious cycle operates between diarrhea and zinc deficiency. Diarrhea
generally entails poor absorption of nutrients due to rapid transit in
the gut, deterioration of the absorptive mucosa and loss of specific
transporters. Diarrhea may produce a secretory state in the small
intestine, preventing or reducing net absorption. In addition to the
pathophysiologic conditions, nutrient wastage is produced during
diarrheal disease of bacterial origin because cellular debris,
intestinal flora proliferation and undigested solids may adsorb
minerals, including zinc, and reduce their bioavailability. Zinc
required in the regeneration of the absorptive mucosa may thus be
sequestered or be insufficient, perpetuating the pathology. Conversely,
in children with low plasma zinc (8.4 µmol/L; 33rd percentile), an
indicator of severe zinc deficiency, there was a greater incidence of
severe diarrhea with fever than in those who had higher plasma zinc
concentrations (Bahl et al. 1998
). In this population,
plasma zinc did not correlate with an index of weight for height,
suggesting that the incidence of gastrointestinal disease and the
degree of zinc depletion were not necessarily linked to a predisposing
poor nutritional status.
It has long been known that prolonged diarrheal disease affects the
absorption of macronutrients and micronutrients, possibly through
damage to the absorptive capacity of the gut (Stern et al. 1980
). In laboratory animals, a model of chronic
osmotic-secretory diarrhea served to demonstrate a reduction in the
absorptive capacity for amino acids (Wapnir et al. 1988
)
and zinc (Lee and Wapnir 1993
). In these studies, the
addition of certain long-chain fatty acids in the diets reversed
zinc malabsorption. However, an amelioration of zinc status by a higher
intake of oils and fats is not realistic for humans in the context of
endemic infectious gastroenteritis in populations of tropical
countries, where diets are low in fat. Carbohydrates probably are the
most accessible macronutrients for most populations. Monosaccharides
and easily digestible glucose polymers enhance zinc intestinal
absorption. Additional milk intake entailing a greater lactose
ingestion may produce age-dependent effects on zinc absorption. In
animal studies, lactose ingestion appears beneficial early in life but
detrimental in mature individuals (Ghishan et al. 1982
,
Wapnir et al. 1989
). These findings provide a cautionary
note for supporting the parsimonious introduction of milk feedings
during recovery from diarrhea and treatment of zinc deficiency.
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Mechanisms involved in the triggering of diarrhea episodes: Possible role of zinc deficiency |
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TOPABSTRACTOverview: Interrelationship...Mechanisms involved in the...Interactions of zinc with...Strategies for redressing the...REFERENCES |
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). In addition to parasites, such as
Giardia, Cryptosporidia and
Cyclospora, bacterial infections, particularly those
produced by V. cholera and E. coli, represent the
most threatening public health hazard in the developing countries.
E. coli may be responsible for ~50% of all worldwide
diarrheal episodes. The mechanisms by which cholera toxin (CT) triggers
diarrhea include not only the stimulation of adenylate and guanylate
cyclases, which evokes chloride secretion, but also another
secretagogue, 5-hydroxytryptamine (serotonin) (Bearcroft et al. 1996
). Enterotoxigenic E. coli strains produce
heat-stable and heat-labile enterotoxins, which have
substantial homology with CT (Gianella 1995
). Activation
of the toxin receptors is mediated through phosphorylation by protein
kinase C, followed by a cascade of reactions leading to the synthesis
of cyclic nucleotides (Crane and Shanks 1996
).
Other more specific underlying mechanisms may be involved in the cycle
of events regarding zinc and diarrheal disease. Cytokines responsible
for induction of acute-phase response, such as interleukin-1
(IL-1), regulate metallothionein mRNA expression (Cousins and Leinart 1988
). The injection of IL-1
produced diarrhea in
66% of zinc-deficient rats but in none of the well-fed animals
(Cui et al. 1997
). This may explain the susceptibility
to infectious diarrhea of individuals with a compromised zinc status.
Another important contribution has been the finding of an
up-regulation of uroguanylin, or guanylate cyclase–activating
peptide II, during experimental zinc depletion. Uroguanylin and the
structurally similar peptide guanylin are activators of guanylate
cyclase C, which leads to the synthesis of cGMP. This cyclic nucleotide
in turn regulates the cystic fibrosis transmembrane regulator, a
mechanism involved in membrane sodium and chloride balance. Guanylate
cyclase C is also one of the targets of one of E. coli
enterotoxins (Blanchard and Cousins 1997
). This subject
is discussed more extensively elsewhere in the symposium.
Therefore, this potential concatenation of events among zinc depletion,
up-regulation of neuropeptides and ultimately secretory conditions
in the intestine may explain why zinc deficiency can easily lead to
diarrheal episodes.
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Interactions of zinc with free radicals and with nitric oxide as related to intestinal function |
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TOPABSTRACTOverview: Interrelationship...Mechanisms involved in the...Interactions of zinc with...Strategies for redressing the...REFERENCES |
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). The role of zinc as an
antioxidant has been predicated on its ability to be an intramolecular
stabilizer, preventing the formation of disulfide bonds and either
displacing or competing with cupric or ferric ions, which trigger the
formation of free radicals (Bray and Bettger 1990
).
However, because the importance of nitric oxide (NO) as a second
messenger became increasingly understood in the past several years, new
connections among gastrointestinal disease, inflammation, free radicals
and tissue damage have entered into consideration regarding the
possibility of zinc playing a role in these processes. NO modulates
inflammation and can act both as a proinflammatory and an
anti-inflammatory agent. Proinflammatory cytokines up-regulate
inducible NO synthase. This mechanism may be activated in sepsis and in
localized infections. Conversely, a reduction in NO synthesis in
endothelia may lead to contraction of endothelial cells, increased
vascular protein leakage and inflammation. In the intestine, there also
is evidence of the delicate balance between the modulation of NO
synthesis and the integrity of the mucosal barrier. Inhibition
of NO synthesis may produce a "dysfunctional" epithelial barrier
with partial loss of protection against the transcellular passage of
potentially deleterious macromolecules, such as antigens, and even
bacterial translocation (Alican and Kubes 1996
). The
role of NO in experimental colitis was also shown to be mediated via
proinflammatory cytokines (Southey et al. 1997
).
The biphasic outcome of NO synthesis in the gut resulting in
proabsorptive or antiabsorptive effects has been shown in vivo by
varying the concentration of the NO precursor L-arginine.
In the perfused rat jejunum, low concentrations of
L-arginine (1–2 mmol/L) have proabsorptive effects,
increasing net water and sodium absorption. At a higher
L-arginine concentration (20 mmol/L), a small secretory
effect could be measured (Wapnir et al. 1997
). These
concentration-dependent proabsorptive and antiabsorptive actions of
NO have been subsequently confirmed (Schirgi-Degen and Beubler 1998
).
It is of greater interest that NO activates the formation of cGMP
(Fig. 2
). In turn, cGMP activates a cGMP-dependent protein kinase C. On
phosphorylation of this enzyme and dephosphorylation of myosin light
chain, cell contraction and relaxation of the interepithelial junctions
occur with an increase in permeability of the barrier. In addition,
protein kinase C acts on transmembrane transporters, resulting in
leakage of chloride and, hence, intestinal secretion and diarrhea. A
similar phenomenon is produced via the formation of cAMP resulting in
secretory conditions (Clancy and Abramson 1995
).
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).
In an attempt to investigate whether zinc acts as an NO scavenger, a
chemical NO-generating system based on the reduction of nitrite
with iodide was exposed to increasing concentrations of zinc chelates
with L-histidine and citrate, using the conversion of
methemoglobin from oxyhemoglobin as an indicator of NO formation.
Concentrations of zinc in the 1–2 mmol/L range reduced 50%
methemoglobin synthesis, suggesting effective scavenging of NO by
soluble zinc complexes (Wapnir et al. unpublished data). It remains to
be determined whether these experimental findings are applicable in
vivo if zinc were to be used as a pharmacologic agent for scavenging of
deleterious free radicals. Zinc as a bishistidine complex has been
found to improve postischemic reperfusion injury in rats (Powell et al. 1994
) and shown to be effective as a myocardial
preservative when added to a cardioplegic solution (Powell et al. 1997
). The potential role of soluble organometallic zinc
complexes as antioxidants and free radical scavengers has been foretold
by Vallee (1995
) in his statement, "Nature apparently
has availed itself of the redox chemistry of the ligand, not the metal,
as a means to control the dynamics of zinc binding."
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Strategies for redressing the risks of zinc deficiency regarding gastrointestinal disease |
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TOPABSTRACTOverview: Interrelationship...Mechanisms involved in the...Interactions of zinc with...Strategies for redressing the...REFERENCES |
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,
Santosham et al. 1996
). Oral rehydration therapy is
probably one of the most cost-effective treatments available for
preventing one of the main consequences of protracted diarrhea, i.e.,
dehydration. How zinc deficiency and the general nutritional status of
the populations at greatest risk play into the picture are more complex
matters. Questions to be resolved in the future, in this regard, could
be viewed in the following sequence of complexity. (1) Is it reasonable to provide zinc supplementation to children at high risk of persistent diarrheal disease? It appears to be very likely that a subpopulation in many developing countries are marginally or definitely zinc deficient and thus at a greater risk of its consequences. Zinc supplementation is attractive as a simple, inexpensive and possibly effective way to cut down on one of the consequences of persistent and repeated bouts of diarrhea, i.e., zinc depletion. Would the inclusion of zinc in oral rehydration solutions be a satisfactory approach? Is it reasonable to argue for an enrichment with zinc of staple foods, possibly together with iron, vitamin A or other critical micronutrients?
(2) If the nutritional status of the population at large, especially its younger segments, is improved, then the need for a specific enrichment becomes less pressing. Therefore, is it ethical to make an effort to only supply "cake," in the form of a zinc supplement, when there is insufficient "bread" for the needy? The importance of sufficient high quality protein intake was pointed out in earlier sections. How to achieve it is certainly not an easy task.
(3) Ideally, the social and physical environments of the populations at greatest risk determine the conditions and the extent to which malnutrition and disease prevail. Industrialized nations have had 150 y of public health progress, which entailed a decline in endemic and epidemic diseases that are often largely preventable with good sanitation and enlightened social policies. If those responsible for advancement in this front in other parts of the world have the determination and if those who can afford to help contribute to the task, the role of the scientists will be simplified. If this ideal situation develops, the application of physiologic and biochemical new findings will not be clouded by the impossibility of putting them into practice.
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FOOTNOTES |
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2 Abbbreviations used: CT, cholera toxin; IL-1, interleukin-1; NO, nitric oxide; NPY, neuropeptide Y.
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TOPABSTRACTOverview: Interrelationship...Mechanisms involved in the...Interactions of zinc with...Strategies for redressing the...REFERENCES |
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